1. Field of the Invention
This invention relates broadly to articles of manufacture for administration of pharmacologically active substances, transdermally and by means of implant (e.g., subdermal implant).
The system comprises a backing member substantially impermeable to the pharmacologically active agent, a pharmacologically active agent reservoir member consisting essentially of a pharmacologically active agent and a carrier therefor and a rate controlling member which is a lamina consisting essentially of a first polymeric composition of matter which consists essentially of at least one C.sub.2 -C.sub.4 lower olefin-C.sub.1 -C.sub.8 alkyl acrylate and/or methacrylate copolymer having 2-90% by weight of alkyl acrylate and/or methacrylate monomeric units, taken alone, or further taken together with, in intimate admixture, a second polymeric composition consisting essentially of a C.sub.2 -C.sub.4 polyalkylene corresponding to the C.sub.2 -C.sub.4 lower alkylene of said copolymer, said second polymeric composition being compatible with said first polymeric composition of matter.
2. The Prior Art
Many prior art articles of manufacture have been disclosed for controlled release delivery of various drugs including transdermal delivery of nitroglycerin and timolol as well as clonidine. Indeed, prior art devices exist for high flux transdermal delivery of drugs over an extended period of time comprising in combination:
(a) an impermeable backing member; PA1 (b) a pharmacologically active agent rate controlling membrane; PA1 (c) a pharmacologically active agent reservoir maintained there between with the reservoir composition comprising a carrier and the pharmacologically active agent; and PA1 (d) means for maintaining the system in pharmacologically active agent transmitting relationship to the skin. PA1 (a) 0.5 to 15% by weight of an ethylenically unsaturated oil, and PA1 (b) a mixture of diethyl O-(2-isopropyl-4-methyl-6-pyrimidinyl)thionosphosphate and diethyl O-(2-isopropyl-4-methyl-6-pyrimidinyl)phosphate, wherein diethyl O-(2-isopropyl-4-methyl-6-pyrimidinyl) thionophosphate is 10 to 90% by weight of said mixture and diethyl O-(2-isopropyl-4-methyl-6-pyrimidinyl)phosphate is 90 to 10% by weight of said mixture." PA1 (i) an impermeable backing member; PA1 (ii) a control membrane lamina consisting essentially of a first polymeric composition of matter which consists essentially of at least one C.sub.2 -C.sub.4 lower olefin-C.sub.1 -C.sub.8 alkyl acrylate and/or methacrylate copolymer having 2-90% by weight of alkyl acrylate and/or methacyrlate monomeric units taken alone or taken further together with, in intimate admixture a second polymeric composition consisting essentially of a C.sub.2 -C.sub.4 polyalkylene corresponding to the C.sub.2 -C.sub.4 lower alkylene of the first polymeric composition, the said second polymeric composition being compatible with the said first polymeric composition of matter; PA1 (iii) a pharmacologically active agent reservoir maintained there between comprising said pharmacologically active agent and a carrier therefor (a) said pharmacologically active agent being physically and chemically compatible with said first polymeric composition of matter and (b) said first polymeric composition of matter being capable of permitting release of said pharmacologically active agent from said pharmacologically active agent reservoir at a rate lower than that previously obtained in prior art articles and from a reservoir containing a concentration of pharmacologically active agent higher than that previously used in prior art articles.
Pharmacologically active agent release rate controlling membranes composed of compositions of matter consisting essentially of olefin-alkyl acrylate copolymers taken alone or further together in intimate admixture with olefin polymers have not been disclosed and are unknown in the prior art.
European Patent 186,071 assigned to Merck and Co., Inc. published on Jul. 2, 1986 discloses a system for administering timolol for an extended period comprising a backing member substantially impermeable to timolol, a timolol reservoir member consisting essentially of timolol as the drug and a carrier therefor and a rate controlling member which can be microporous polypropylene, ethylene-vinyl acetate copolymer, a silicone polymer or a polyurethane polymer. The European Patent 186,071 indicates that by the system disclosed transdermal application of timolol may be accomplished with substantially no irritation to the skin.
U.S. Pat. No. 4,060,084 assigned to Alza Corporation discloses a method and therapeutic system in the form of a bandage for providing chemotherapy transdermally by administering certain drugs to unbroken skin in an initial priming dose that quickly brings the systemic concentration of drug to a therapeutic level, followed by a substantially constant dosage that holds the level, U.S. Pat. No. 4,060,084 discloses a bandage which is a four-layer laminate of, from the top: a protective backing; a drug reservoir lamina that is a source of constant dosage; a microporous membrane that controls the constant dosage rate; and an adhesive layer that is the source of the priming dose and the means by which the bandage is attached to the skin. However, disclosed for use in fabricating the membrane are polymers such as polypropylene, polyethylene, polyvinyl chloride, cellulose acetate, cellulose nitrate, polycarbonates and polyacrylonitrile. No mention is made of polyacrylates or acrylate-polyolefin copolymers for use as the controlling membrane in U.S. Pat. No. 4,060,084.
U.S. Pat. No. 4,615,699 issued on Oct. 7, 1986 assigned to Alza Corporation discloses a high flux transdermal nitroglycerin therapeutic system capable of delivering nitroglycerin through intact human skin at rates of 40 micrograms/cm.sup.2 hr. and preferably in the range of 50-150 micrograms/cm.sup.2 hr. It is indicated that ethanol delivered at a rate of from 250-500 micrograms/cm.sup.2 hr. is employed as a permeation enhancer for the nitroglycerin and a rate controlling membrane formed from ethylene vinyl acetate having a vinyl acetate content greater than 11% and preferably between 12-18% "provides the appropriate rate control for both the drug and the permeation enhancer", U.S. Pat. No. 4,615,699 does not infer the utilization of the copolymers or copolymer-polymer mixtures which form the basis of the instant invention.
U.S. Pat. No. 4,201,211 issued on May 6, 1980 discloses a therapeutic system in the form of a skin patch that administers clonidine transdermally in an initial priming dose of 10 to 30 micrograms/cm.sup.2 of skin that brings the concentration of clonidine in the blood to a level sufficient to elicit alpha-adrenergic stimulation without intolerable side effects followed by a substantially constant continuous dosage in the range of 0.1 to 100 micrograms/hr. that maintains the level. The system is a four-layer laminate of, from the top: a protective backing; a gelled mineral oil-polyisobutene-clonidine reservoir lamina that is the source of the clonidine for the continuous constant dosage; a microporous membrane that controls the constant dosage rate; and a gelled, mineral oil-polyisobutene-clonidine contact adhesive layer that is the source of the clonidine for the priming dose and the means by which the system is attached to the skin, U.S. Pat. No. 4,201,211 does not disclose the use or infer the use of the acrylate-olefin copolymer for the control membrane; that is, the membrane that controls the dosage rate.
Indeed, nothing in the prior art discloses the utilization in control release pharmacologically active drug devices of a control membrane composed of an acrylate-olefin copolymer or mixtures thereof with polyolefins as described and claimed in the instant invention.
Shah, et al, Journal of Biomaterials Applications, Vol. 1, October, 1986, pages 239-273 discloses a multi-layered laminated polymeric structure for controlled drug delivery in which a layer of vinyl chloride copolymer or terpolymer containing the drug is sandwiched between two or more layers of polymeric films. Shah, et al discloses that the drug is released from the device at a controlled rate by a process of diffusion through the reservoir and one of the outer layers which can function as a rate controlling membrane. Shah, et al discloses at page 259, that:
"The rate controlling membranes investigated were olefinic copolymers containing a polar modifier," PA0 "A drug delivery device for the controlled, oral administration of water-soluble prednisolone is prepared as follows: first, a plurality of drug reservoirs comprising porous, discrete particles of polymerized poly(vinyl chloride) of about 100 microns diameter are prepared by mixing 100 g of suspension grade poly(vinyl chloride) resin with 50 g of octyl diphenyl phosphate and 10 g of prednisolone disodium phosphate at room temperature into a sticky, wet mass. Next, the temperature of the mixture is raised to 80.degree. C. for about 3 to 7 minutes, while stirring, to form dry, free flowing, discrete drug reservoirs. The reservoirs are uniformly dispersed through a matrix by mixing 50 g of reservoirs containing the prednisolone with 140 g of polydimethylsiloxane, 10 g of silicone oil, and 0.5 g of stannuous octoate. After mixing the ingredients, the mixture is charged into pill molds and allowed to cure for 30 minutes. Oral administration of the resulting device yields a controlled essentially constant rate of release of prednisolone phosphate to the gastrointenstinal tract to give a more uniform blood level of prednisolone over a longer period of time than is achieved when prednisolone alcohol is administered by standard prior art pills." PA0 "In an animal collar for controlling fleas and ticks on cats and dogs, a part of said animal collar being formed of a solid vinyl or vinylidene polymer matrix in which is dispersed a pesticidal composition, an improved pesticidal composition consisting essentially of: PA0 "The macromolecular substance preferably has a weight of more than 1000; it is selected from the homopolymers and copolymers obtained starting from vinyl chloride, vinyl acetate, vinyl acetals, vinylalcohol, vinylbenzene and divinylbenzene and vinylidene chloride; the copolymers may, in addition, contain additional components such as ethylenic, propylenic, butadienic, isoprenic, acrylic and methacrylic components. PA0 Preferably, the macromolecular substance is a polymer or copolymer of a vinyl compound such as, for example, the polyvinyl halides. The particularly preferred macromolecular substances are polymers or copolymers of vinyl chloride. PA0 The macromolecular substance preferably contains one or more plasticizers. PA0 The plasticizers are liquid esters with a vapour pressure of less than 0.0001 mm/Hg at 25.degree. C. Some nonrestrictive examples of plasticizers are: diethyl, dimethyl, dipropyl, dibutyl, dihexyl, dioctyl and didecyl phthalate, dibutyl, diamyl, dinonyl, dioctyl, and didecyl adipate, dipropyl, dibutyl, dibenzyl and dioctyl sebacate, diethyl, dipropyl and dibutyl citrate, triphenyl and tricresyl phosphate and the triglycerides. PA0 The preferred plasticizers are dibutyl phthalate and dioctyl adipate, which make it possible to obtain an arrangement with good flexibility, on the surface of which the active principle appears rapidly and regularly."
The Shah, et al paper was published subsequent to the filing date of parent application, Ser. No. 847,635 filed on Apr. 3, 1986, now U.S. Pat. No. 4,751,438.
Furthermore, Canadian Patent No. 930,668 discloses a bandage for administering drugs comprised of a backing member, a pressure sensitive adhesive, and at least one reservoir disposed between the backing member and pressure sensitive adhesive. The reservoir is comprised of a systemically active drug formulation confined within a wall member, the wall member being formed from a drug release controlling material. The reservoir can be in the form of discrete microcapsules or distinct reservoir compartments or layers. The reservoir can also be in the form of walled containers having one or more interior drug-containing chambers, as well as solid matrices having a systemically active drug distributed therethrough. The Canadian patent discloses a wide variety of materials which can be used to form the reservoir. Among the materials mentioned are silicone rubbers, hydrophilic polymers of monoesters of an olefinic acid, polyvinylalcohol, polyvinylacetate, plasticized polyvinylchloride, plasticized nylon, collagen, modified collagen, gelatin, and waxes such as polyethylene wax, oxidized polyethylene wax, hydrogenated castor oil and the like, with the silicone rubbers being preferred. The Canadian patent does not contain any examples showing the use of plasticized polyvinyl chloride.
Similarly, Zaffaroni, U.S. Pat. No. 3,921,636 issued on Nov. 25, 1975 discloses a drug delivery device for administering a drug at a controlled rate for a prolonged period of time comprising a plurality of reservoirs containing drug distributed through a matrix. The reservoirs and the matrix are formed of materials permeable to passage of the drug. The rate of drug permeation from the reservoir is lower than the rate of permeation through the matrix so that release from the reservoir is the drug release controlling step. Thus, Example 6, at column 15, lines 5-30 of U.S. Pat. No. 3,921,636 relates to a polyvinyl chloride resin containing plasticizer and prednisolone disodium phosphate thusly:
U.S. Pat. No. 4,150,109 (Dick, et al) issued on Apr. 17, 1979 entitled "Device for Protecting Animals from Ectoparasites" discloses and claims:
wherein the "solid vinyl . . . matrix" and the plasticizers are described thusly:
Furthermore, as is well known, polyvinyl chloride (PVC) is never used alone, but is always mixed with other ingredients before being processed. Polyvinyl chloride appeared initially to be an unpromising resin because of its thermal instability and high rigidity. PVC, however, was then discovered to form a rubber-like material when dissolved hot in high boiling solvents known as plasticizers and cooled to room temperature. PVC is now available in a number of different physical forms and types, and its manufacture depends on the form desired. Thus, PVC is available as a vinyl latex, a dispersion resin, or a general purpose resin. PVC latexes are true colloidal dispersions of submicrometer particles in water, stabilized by a surfactant system, and need plasticizers in order to form a continuous film. The PVC is vinyl latex is manufactured by emulsion polymerization.
Dispersion resins are produced by emulsion polymerization and are mixed with plasticizers to form a colloidal dispersion. Such dispersions are known as plastisols and are easily handled and readily pourable. When heated to a temperature of about 140.degree. to 177.degree. C., the plastisol is transformed to a homogeneous melt which, upon cooling to below 50.degree. C., results in a tough flexible product. The PVC resins made by emulsion polymerization are hard spheres of particle size between about 0.05 and 20 microns, such as between 1 and 20 microns. They do not have the ability to absorb plasticizers. Therefore, a mixture containing, for example, 30% plasticizer and 70% PVC resin, produces a flowable liquid, known as "plastisol".
General purpose PVC resins are made by mass and suspension polymerization process, and comprise the largest amount of PVC resins produced, such as at least 80% of all PVC resins, and are used chiefly to make so-called 100% vinyl products by a variety of molding and extrusion techniques. Resins intended for flexible applications should have good uptake of plasticizer in a dry blending operation and contain more than 25% of a plasticizer system. PVC compounds that contain less than 25% plasticizers are referred to as semirigid compounds. The PVC resins manufactured by suspension and bulk polymerization are 50 to 200, such as 100 to 150 microns in diameter, and are like sponges. They are capable of absorbing large amounts of plasticizers, so that even a 50% plasticizer, 50% PVC resin composition would result in a non-flowing, solid material.